Stimulant sensitization, i.e., enhanced behavioral and neurochemical responsiveness to drugs such as cocaine or amphetamine, resulting from prior exposure, has recently received considerable attention as a possible key factor in the development of drug addiction. Although it is assumed to represent a unidirectional response to repeated administration, recent findings in our laboratory suggest that, when near-maximal sensitization is achieved, additional administration of cocaine results in an "on-off", oscillatory pattern of responsiveness. This has been seen both neurochemically and behaviorally and may represent an important factor in the extreme variability known to be characteristic of stimulant sensitization and vulnerability to drug addiction. The present application proposes principally to study the effects of repeated cocaine treatment on dopamine efflux from striatal and nucleus accumbens brain slices and focuses on the questions of: 1) the factors which determine when sensitization changes from a unidirectional to an oscillatory phenomenon; and 2) the mechanisms which might underlie that change. The application also addresses these same questions behaviorally and by means of in vivo microdialysis. The first question, which is approached in Experimental Series I, examines the importance of variables such as dose of cocaine, reactivity of the animal, stress and gender. The question of mechanisms, examined in Experimental Series II, focuses on dopamine synthesis and reuptake as well as the possibility that a waxing and waning of cocaine pharmacokinetic factors could play a role in the switch from unidirectional sensitization to an "on-off" pattern of responding.